Evaluation and treatment of fatigue in cancer patients requires a multidisciplinary approach because it has many possible etiologies and several contributing factors. A comprehensive approach is required, especially for patients with moderate to severe fatigue, so that all possible contributing factors can be determined and an appropriate treatment plan can be created. New agents for the management of fatigue need to be evaluated in large, controlled, clinical trials. The short- and long-term effects of an exercise program on the fatigue levels and overall physical performance of cancer patients should be assessed in new studies. Clearly, much more research is needed not only to identify factors responsible for the fatigue but also to develop effective interventions for cancer-related fatigue.